Mobile psychiatry: Personalised Ambient Monitoring for the mentally ill

Mental health has long been a neglected problem in global healthcare. The social and economic impacts of conditions affecting the mind are still underestimated. However, in recent years it is becoming more apparent that mental disorders are a growing global concern that is not to be trivialised. Considering the rising burden of psychiatric illnesses, there is a necessity of developing novel services and researching effective means of providing interventions to sufferers. Such novel services could include technology-based solutions already used in other healthcare applications but are yet to make their way into standard psychiatric practice. This thesis presents a study on how pervasive technology can be utilised to devise an “early warning” system for patients with bipolar disorder. The system, containing wearable and environmental sensors, would collect behavioural data and use it to inform the user about subtle changes that might indicate an upcoming episode. To test the feasibility of the concept a prototype system was devised, which was followed by trials including four healthy volunteers as well as a bipolar patient. The system included a number of sensory inputs including: accelerometer, light sensors, microphones, GPS tracking and motion detectors. The experiences from the trials led to a conclusion that a large number of sensors may result in incompliance from the users. Therefore, a separate investigation was launched into developing a methodology for detecting behavioural patterns in inputs possible to collect from a mobile phone alone. The premise being that a phone is an everyday use appliance and is likely to be carried and accepted by the patient. The trial revealed that monitoring GPS tracks and Bluetooth encounters has the potential of gaining an insight into a person’s social and behavioural patterns, which usually are strongly influenced by the course of bipolar disorder. Lessons learned during these proceedings amounted to a clearer concept of how a future personalised ambient monitoring system could improve the outcome of treatment of bipolar disorder as well as other psychiatric conditions

Mobile psychiatry: Personalised Ambient Monitoring for the mentally ill

Mental health has long been a neglected problem in global healthcare. The social and economic impacts of conditions affecting the mind are still underestimated. However, in recent years it is becoming more apparent that mental disorders are a growing global concern that is not to be trivialised. Considering the rising burden of psychiatric illnesses, there is a necessity of developing novel services and researching effective means of providing interventions to sufferers. Such novel services could include technology-based solutions already used in other healthcare applications but are yet to make their way into standard psychiatric practice. This thesis presents a study on how pervasive technology can be utilised to devise an “early warning” system for patients with bipolar disorder. The system, containing wearable and environmental sensors, would collect behavioural data and use it to inform the user about subtle changes that might indicate an upcoming episode. To test the feasibility of the concept a prototype system was devised, which was followed by trials including four healthy volunteers as well as a bipolar patient. The system included a number of sensory inputs including: accelerometer, light sensors, microphones, GPS tracking and motion detectors. The experiences from the trials led to a conclusion that a large number of sensors may result in incompliance from the users. Therefore, a separate investigation was launched into developing a methodology for detecting behavioural patterns in inputs possible to collect from a mobile phone alone. The premise being that a phone is an everyday use appliance and is likely to be carried and accepted by the patient. The trial revealed that monitoring GPS tracks and Bluetooth encounters has the potential of gaining an insight into a person’s social and behavioural patterns, which usually are strongly influenced by the course of bipolar disorder. Lessons learned during these proceedings amounted to a clearer concept of how a future personalised ambient monitoring system could improve the outcome of treatment of bipolar disorder as well as other psychiatric conditions

Global gene expression profiling of healthy human brain and its application in studying neurological disorders

The human brain is the most complex structure known to mankind and one of the greatest challenges in modern biology is to understand how it is built and organized. The power of the brain arises from its variety of cells and structures, and ultimately where and when different genes are switched on and off throughout the brain tissue. In other words, brain function depends on the precise regulation of gene expression in its sub-anatomical structures. But, our understanding of the complexity and dynamics of the transcriptome of the human brain is still incomplete. To fill in the need, we designed a gene expression model that accurately defines the consistent blueprint of the brain transcriptome; thereby, identifying the core brain specific transcriptional processes conserved across individuals. Functionally characterizing this model would provide profound insights into the transcriptional landscape, biological pathways and the expression distribution of neurotransmitter systems. Here, in this dissertation we developed an expression model by capturing the similarly expressed gene patterns across congruently annotated brain structures in six individual brains by using data from the Allen Brain Atlas (ABA). We found that 84% of genes are expressed in at least one of the 190 brain structures. By employing hierarchical clustering we were able to show that distinct structures of a bigger brain region can cluster together while still retaining their expression identity. Further, weighted correlation network analysis identified 19 robust modules of coexpressing genes in the brain that demonstrated a wide range of functional associations. Since signatures of local phenomena can be masked by larger signatures, we performed local analysis on each distinct brain structure. Pathway and gene ontology enrichment analysis on these structures showed, striking enrichment for brain region specific processes. Besides, we also mapped the structural distribution of the gene expression profiles of genes associated with major neurotransmission systems in the human. We also postulated the utility of healthy brain tissue gene expression to predict potential genes involved in a neurological disorder, in the absence of data from diseased tissues. To this end, we developed a supervised classification model, which achieved an accuracy of 84% and an AUC (Area Under the Curve) of 0.81 from ROC plots, for predicting autism-implicated genes using the healthy expression model as the baseline. This study represents the first use of healthy brain gene expression to predict the scope of genes in autism implication and this generic methodology can be applied to predict genes involved in other neurological disorders

Depression in youth and adults : etiology, outcomes, and comorbidities

Depression is a common and debilitating mental disorder characterized by low mood, loss of interest in activities, and long-lasting functional impairment. It is a worldwide psychiatric illness with a wide range of ages of onset, and it occurs about twice as often in women than men. However, most large observational studies have focused on adult populations, leaving pediatric depression largely unexplored. Depressive disorder is linked to poorer physical health and increased comorbidity and mortality, particularly by suicide. This mental condition is the result of a complex interaction between environmental, social, genetic, physiological, and psychological influences, with many risk factors and underlying mechanisms still unknown. This thesis leverages epidemiological statistics and the availability of nationwide registers in Sweden to enhance the understanding of depression in children, adolescents, and adults, exploring adverse health outcomes, psychiatric and somatic comorbidities, potential risk factors, and melatonin treatment for sleep disturbances. In Study I, we described the association of pediatric depression with a wide range of subsequent somatic conditions and premature death, while also exploring the potential role of psychiatric comorbidities. Compared to the general population, individuals diagnosed with depression during youth displayed higher risks for 66 of the 69 somatic diagnoses under investigation (including self-harm, endocrine and metabolic disorders, and sleep disturbances), as well as elevated risks for mortality, particularly for death by intentional self-harm. When adjusted for psychiatric comorbidity, associations were attenuated but persisted. This study provides new insights into the relationships between psychiatric and somatic disorders among a young population, increasing awareness about the burden of pediatric depression and providing a foundation for future research. In Study II, we investigated the link between early-life infections and the risks of depression and self-harm during adolescence and early adulthood. Increased risks of the outcomes were observed among individuals exposed to childhood infections, compared to the rest of the population. When adjusting for familial influences, risks were considerably attenuated and no strong association persisted. Our findings show that childhood infections may not be involved in the etiology of later depression and self-harm, and highlight the importance of identifying these genetic and environmental risk factors shared between family members, which represent potential targets for interventions. Study III explored the underlying factors contributing to the comorbidity of depression and endocrine-metabolic disorders. A family design was applied to investigate the familial co-aggregation of these medical conditions, while quantitative genetic modeling was used to quantify the relative contribution of genetic and environmental influences to the familial liability. We found evidence of shared etiology to the co-occurrence of depression and endocrine-metabolic conditions, which was primarily due to genetics for non-autoimmune conditions, and to unique environmental factors for autoimmune disorders, especially for type 1 diabetes. These findings expand current knowledge on the etiological sources of these comorbidities, which could guide future research aiming at identifying underlying pathophysiological mechanisms. In Study IV, we examined whether melatonin use in children and adolescents with sleep disturbances was associated with a reduced risk of self-harm and unintentional injuries. Risks of the outcomes were assessed in periods before and after melatonin-treatment initiation, among youth with and without psychiatric disorders, and across sexes, injury types, psychiatric disorder diagnoses, and age groups. Melatonin-use initiation was associated with reduced risks of self-harm among adolescent females with depression and anxiety disorders, suggesting that sleep interventions may be an important component to reduce risk of self-injurious behavior in this pediatric population. In conclusion, this thesis contributes to the understanding of depression in youth and adults, highlighting its extensive comorbidity and burden of disease, and posing quality-of-life and public health challenges. Our findings underscore an urgent need for screening, prevention, and early intervention of depression, particularly in young patients, as well as for adequate health care resources to treat this mental illness and its psychiatric and somatic comorbidities

Genetic vulnerability, environmental exposures and neurodevelopmental disorders : clinical insights and in-vitro consequences

An understanding of how different genetic backgrounds and environmental exposures interact and contribute to diverse medical conditions like neurodevelopmental disorders (NDDs), is key to better health outcomes. A considerable overlap exists in the underlying genetics and physiology, often leading to their co-diagnoses. There is a lack of robust biomarkers for ASD and ADHD. Furthermore, no efficient resource exists to evaluate potential gene-environment interactions during early human neurodevelopment. This thesis addressed these knowledge gaps through five clinical and in-vitro studies. Study I explored the utility of genetic information from exome sequencing in predicting intervention outcomes of a social skills group training (SSGT) clinical trial for ASD. A genetic score was developed for common and rare variants in relevant genetic pathways, followed by generating a predictive machine learning (ML) model for individual responses. Variant carriers demonstrated significantly less improvement after standard care at postintervention. A higher rare variant genetic score for synaptic transmission was linked to less efficacy after SSGT at follow-up, while an opposite effect was observed for regulation of transcription from RNA polymerase II. The ML model emphasised the importance of rare variants in predicting intervention outcomes. Study II deployed urine-based untargeted metabolomics to investigate ASD-related biomarkers in a twin cohort with ultra-high performance liquid chromatography and mass spectrometry (UHPLC-MS). For the first time, any associations with autistic traits were also evaluated. No metabolite was found to be significantly associated with ASD. Based on nominal significance, an elevation in phenylpyruvate and taurine, and a decline in carnitine were detected, amongst others. These were found to be enriched in the arginine and proline metabolism pathway. More nominally significant metabolites were associated with autistic traits, and indole-3-acetate was positively associated with autistic traits within twin pairs. Study III also utilised a twin cohort to detect urinary and faecal metabolites associated with ADHD using nuclear magnetic resonance (NMR) and UHPLC-MS, respectively. Males with ADHD had increased levels of urinary hippurate, a metabolite produced by microbial-host co-metabolism. Hippurate was also negatively associated with intelligence quotient (IQ) levels in males and differentially associated with faecal metabolites from the gut microbiome. ADHD faecal profiles were characterised by higher levels of 1-stearoyl-2-linoleoyl-snglycerol (SLG), flavine adenine dinucleotide (FAD) and 3,7-dimethylurate. Reduced levels of aspartate, xanthine, orotate and other metabolites were also detected. Study IV dissected the impact of six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine and zinc deficiency) in human induced pluripotent stem cell (iPSC) derived neuronal progenitors after differentiation for 5 days using the fractional factorial experimental design (FFED) coupled with RNA-sequencing. This was followed by a stratified analytical approach. Several gene and pathway level changes, that were both convergent and divergent for the environmental factor exposures, were identified. Pathways related to synaptic function and lipid metabolism were significantly elevated by lead and fluoxetine, respectively. Furthermore, fluoxetine increased the levels of several fatty acids when validated with direct infusion electrospray ionisation mass spectrometry (ESI-MS). Study V evaluated the differential in-vitro effects of four commonly prescribed selectively serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, sertraline and paroxetine) in iPSC-derived neuronal progenitors. Total reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels were determined at day 5 and 28 of differentiation. Concurrently, untargeted metabolomics was performed using ESI-MS. Sertraline and paroxetine significantly decreased ROS and ATP levels. Sertraline mediated early metabolite changes at day 5, while both sertraline and paroxetine drove such effects at day 28. Combined effects were driven by LPC 18:0 and LPC 16:0. Overall, metabolites were enriched in phospholipid biosynthesis and amino acid metabolism pathways. In conclusion, this thesis highlighted that genetic information can be used as an indicator for ASD interventions, encouraging further exploration. Urine and faecal metabolites are potential biomarkers for ASD and ADHD, pending validation. A multiplexable resource for studying gene-environment interactions was developed, along with a rich dataset outlining molecular changes in ASD. Lastly, the thesis demonstrated that different SSRIs elicit both shared and unique in-vitro responses, with a need to evaluate probable in-utero effects. The findings can guide future clinical studies to generate greater insights into ASD, ADHD and other conditions with aberrant neurodevelopmental trajectories

Cognitive Maps

undefine

Size and burden of mental disorders: A population based perspective

Die klinische Forschung zu Häufigkeit und Krankheitslast psychischer Störungen ist meist in mehrerer Hinsicht nicht repräsentativ. Insbesondere die Tatsache, dass die untersuchten Patienten sich von sich aus in Behandlung begeben, bedeutet eine gewisse Selektion (z.B. überdurchschnittlich motivierte). Mit wie vielen Fällen haben wir es aber zu tun, wenn man auch diejenigen berücksichtigt, die kein aktives Hilfesuch-Verhalten zeigen? Und wie hoch ist die in klinischen Stichproben offensichtliche individuelle Krankheitslast psychischer Störungen auf einer gesellschaftlichen Ebene – auch im Vergleich mit körperlichen Erkrankungen – einzuschätzen? Ansätze für solche Hochrechnungen und die Abschätzung von Häufigkeit, Störungskosten und Behandlungsbedarf psychischer Störungen müssen epidemiologisch anhand von Daten aus der Allgemeinbevölkerung geklärt werden. Die vorliegende Habilitationsschrift basiert auf Publikationen, die in meiner Arbeitsgruppe „Epidemiologie und Versorgungsforschung“ am Lehrstuhl für Klinische Psychologie und Psychotherapie zwischen 2001 und 2006 entstanden sind. Die entsprechenden Befunde und Implikationen wurden und werden nicht nur in der Klinischen Psychologie, sondern auch in Nachbardisziplinen (z.B. Psychiatrie, Epidemiologie, Occupational Health Psychology, Gesundheitsökonomie, Versorgungsforschung) sowie in der nicht-wissenschaftlichen Öffentlichkeit (z.B. Gesundheitsberichterstattung, Versorgungsplanung) zur Kenntnis genommen und zitiert. In den vorgestellten Arbeiten habe ich zunächst – erstmals für Deutschland – auf der Grundlage bevölkerungsbezogener Daten bundesrepräsentative Befunde zur Verbreitung psychischer Störungen herausgestellt (z.B. Jacobi, Wittchen et al., 2004; Jacobi, Hoyer & Wittchen, 2004; Jacobi, Klose & Wittchen, 2004). Zum zweiten beschäftigte ich mich mit der internationalen Befundlage, indem ich mich an der Koordination eines internationalen und multidisziplinären Forscher-Netzwerkes beteiligte, das eine umfassende Abschätzung der Größenordnung im Sinne von Verbreitung und Kosten für die EU vorgenommen hat (Wittchen & Jacobi, 2005). Vor diesem Hintergrund habe ich zum dritten ausgewählte Fragestellungen zum Zusammenhang zwischen psychischen Störungen und körperlichen Erkrankungen bzw. zur Stärke und zu Konsequenzen solcher Komorbidität verfolgt (z.B. Goodwin, Jacobi & Thefeld, 2003; Sareen, Jacobi et al., 2006). Die Habilitationsschrift verdeutlicht nicht nur die eminente Größenordnung und Krankheitslast psychischer Störungen (z.B. reduzierte Lebensqualität, Beeinträchtigungen, Krankheitskosten, Verschlechterung des gesundheitlichen Outcomes bei körperlichen Erkrankungen). Sie eröffnet auch neue wissenschaftliche Perspektiven ihrer Erforschung, z.B. im Hinblick auf Prävention und Behandlungsbedarf, oder hinsichtlich der Verschränkungen mit Prozessen körperlicher Morbidität.This Habilitation-Thesis, based on 10 peer-reviewed publications (2001-2006), presents findings on size and burden of mental disorders in the community. First, following an introductory discussion of methodological aspects in epidemiological studies, an overview of the prevalence of mental disorders in Germany and Europe is given (Part A). As Examples for socio-economic determinants of mental disorders, some analyses on gender differences and a comparison between West and East Germany are presented (Part B). Further, it is shown that mental disorders are costly (in terms of disability adjusted life years as well as in terms of direct and indirect monetary burden) (Part C). This refers also to the interplay between mental disorders and somatic conditions: comorbid cases show significantly poorer outcomes (reduced health related quality of life, work loss and disability, help-seeking behaviour) (Part D)

Understanding cone photoreceptor dystrophies : from animal models to engineered patient-derived retinal tissues

La vision est considérée comme un des sens les plus importants, prenant en charge environ 80% des perceptions que nous recevons dans notre vie quotidienne. Les photorécepteurs de type cônes sont responsables de la vision centrale de haute résolution et en couleurs, et leur dégénérescence est souvent la cause de la perte de vision dans les maladies dégénératives rétiniennes (RDs). Les RDs sont un groupe hétérogène de maladies affectant des millions de personnes dans le monde, qui pour le moment sont pour la plupart sans aucune option thérapeutique. Les modèles animaux sont extrêmement utiles pour étudier le développement ou la dégénérescence de la rétine, ainsi que pour comprendre les mécanismes moléculaires des maladies génétiques héréditaires affectant les photorécepteurs. La modélisation des maladies dégénératives et du développement peut être particulièrement difficile, spécialement dans le cas de maladies humaines rares et complexes pour lesquelles aucun modèle animal exhaustif n'est disponible. De nos jours, la génération et le maintien de modèles de maladies humaines permettant une analyse approfondie du mécanisme moléculaire représente un grand défis . La technologie des cellules souches possède un grand potentiel dans la modélisation des maladies et représente un outil puissant pour générer des modèles évolutifs, sans l’utilisation d’animaux qui peuvent illustrer plus précisément les phénotypes cliniques de maladies humaines complexes. Nous avons développé un protocole pour différencier les cellules souches pluripotentes (PSCs) en feuillets rétiniens (RSs), qui sont des tissus polarisés et multicouches contenant des photorécepteurs cône et exprimant les marqueurs spécifiques du segment externe (OS), du cilium connecteur (CC) et du noyau. En utilisant à la fois des modèles de souris et des modèles humanisés à base de cellules souches, nous avons étudié le rôle de BMI1 dans les photorécepteurs matures. La protéine du groupe Polycomb Bmi1 est connue pour ses fonctions neuroprotectrices en contrôlant la sénescence et l'apoptose, et est exprimée à la fois dans le progéniteur rétinien et les neurones, mais on en sait peu sur son rôle spécifique dans la rétine adulte. Elle a été récemment associée à des troubles neurodégénératifs d'apparition tardive, et elle pourrait avoir un rôle dans la pathologie des RDs d'apparition tardive, comme la dégénérescence maculaire liée à l'âge (DMLA). Nous avons montré que les photorécepteurs cône et les neurones bipolaires sont générés normalement mais subissent ensuite une dégénérescence rapide chez les souris Bmi1-/- par nécroptose associée à Rip3. La dégénérescence était associée à des anomalies de compactage de la chromatine, à l'activation des répétitions en tandem et au stress oxydatif. De plus, nous montrons que BMI1 est préférentiellement exprimé dans les cônes au niveau des foyers hétérochromatiques dans la rétine humaine. Son inactivation dans les cellules souches embryonnaires humaines (hESCs) a altéré la différenciation terminale du cône et a entraîné des anomalies de compactage de la chromatine, l'activation des répétitions en tandem et l'induction de P53. Ces résultats fournissent un mécanisme expliquant comment une carence en Bmi1 conduit à la dégénérescence des cônes et révèlent des fonctions biologiques conservées et des différences pour Bmi1 dans la biologie des photorécepteurs entre la souris et l'homme. En utilisant un modèle humain basé sur les cellules souches pluripotentes induites (iPSCs), nous avons ensuite étudié le processus dégénératif chez les patients atteints de ciliopathies, un groupe de maladies génétiques hétérogènes affectant les protéines impliquées dans la structure et la fonction du cil primaire, qui sont fréquemment accompagnée d'une dégénérescence rétinienne. Nous générons des feuillets rétiniens dérivés d'iPSCs à partir de patients atteints de deux ciliopathies, les syndromes de Meckel-Gruber (MKS) et de Bardet-Biedl (BBS). Les photorécepteurs ciliopathiques présentaient des altérations communes significatives dans l'expression de centaines de gènes de développement. De plus, ils ont montré plusieurs anomalies dans la formation et le maintien du cilium interne, le positionnement du centriole mère, l'activation d'une réponse au stress aux protéines mal repliées, instabilités génomiques et l'accumulation de dommages à l'ADN. Cette étude révèle comment la combinaison des technologies de reprogrammation cellulaire et d'organogenèse avec le séquençage de nouvelle génération permet d'élucider les mécanismes moléculaires et cellulaires impliqués dans les troubles dégénératifs et développementaux de la rétine humaine. La même approche, combinant la différenciation en RSs avec des techniques de séquençage du génome à large spectre, pourrait être appliquée pour modéliser de nombreuses maladies génétiques, développementales et dégénératives affectant les photorécepteurs. Il peut également aider à élucider les mécanismes moléculaires sous-jacents à ces maladies, au criblage de médicaments de composés ayant des effets thérapeutiques potentiels et à prédire les effets secondaires des médicaments.Vision is considered the most important sense, taking on about 80% of the perceptions we receive in our everyday life. Cone-photoreceptors are responsible for high-resolution central vision and color discrimination, and their degeneration is frequently the cause of vision loss in retinal degenerative diseases (RDs). RDs are a heterogeneous group of diseases affecting millions of people worldwide, which at the moment are mostly without any therapeutic option. Animal models are extremely useful in studying the retina's development or degeneration and understanding the molecular mechanisms in inherited genetic disease affecting photoreceptors. Modeling human developmental and degenerative diseases can be particularly challenging, especially in the case of rare and complex diseases where no exhaustive animal models are available. Generation of sustainable human disease models that allow in-depth analysis of the molecular mechanism is one of the big challenges nowadays. Stem cell technology holds great potential in disease modeling and represents a new powerful tool for generating scalable and animal-free models that can more accurately illustrate clinical phenotypes of complex human diseases. We developed a protocol to differentiate pluripotent stem cells (PSCs) into retinal sheets (RSs), which are polarized, multi-layered tissues containing cone photoreceptors and expressing outer segment (OS), connecting cilium (CC), and nuclear specific markers. Using both mouse and stem cells-based humanized models, we first investigate the role of BMI1 in mature photoreceptors. The Polycomb group protein Bmi1 is known for its neuroprotective functions by controlling senescence and apoptosis and is expressed in both retinal progenitor and neurons, but little is known about its specific role in the adult retina. It has been recently linked to late-onset neurodegenerative disorders, and it could have a role in the pathology of late-onset RDs, such as Age-related Macular Degeneration (AMD). We showed that cone photoreceptors and bipolar neurons are generated normally but then undergo rapid degeneration in Bmi1-/- mice through Rip3-associated necroptosis. Degeneration was associated with chromatin compaction anomalies, activation of tandem-repeats, and oxidative stress. Furthermore, we show that BMI1 is preferentially expressed in cones at heterochromatic foci in the human retina. Its inactivation in human embryonic stem cells (hESCs) impaired cone terminal differentiation and resulted in chromatin compaction anomalies, activation of tandem-repeats, and P53 induction. These findings provide a mechanism explaining how Bmi1 deficiency leads to cone degeneration and reveal conserved biological functions and differences for Bmi1 in photoreceptor biology between mouse and man. Using an induced Pluripotent Stem Cells (iPSCs) based human model, we then investigate the degenerative process in patients with ciliopathies, a group of heterogeneous genetic diseases affecting proteins involved in primary cilium structure and function frequently accompanied by retinal degeneration. We generate iPSC-derived retinal sheets from patients affected by two ciliopathies, Meckel-Gruber (MKS) and Bardet-Biedl syndromes (BBS). Ciliopathic photoreceptors displayed significant common alterations in the expression of hundreds of developmental genes. Moreover, they showed several anomalies in the formation and maintenance of cilia, the mother centriole's positioning, the activation of a stress response to misfolded proteins, genomic instabilities, and DNA damage accumulation. This study reveals how combining cell reprogramming and organogenesis technologies with next-generation sequencing enables the elucidation of molecular and cellular mechanisms involved in human retinal degenerative and developmental disorders. The same approach, combining photoreceptor sheet differentiation and wide-genome expression profile, could be applied to model many genetic, developmental, and degenerative diseases affecting photoreceptors. It may help elucidate the molecular mechanisms underlining these diseases, drug screening of compounds with potential therapeutic effects, and predict drug side effects